The present invention relates to arylpiperidine derivatives having antipsychotic effect.
Antipsychotic agents are used not only for treating schizophrenia but also for treating problem behaviors associated with cerebrovascular diseases or senile dementia (e.g. aggressive behaviors, psychogenic excitement, ecdemomania and delirium). However, dopamine D2 receptor antagonists, conventional antipsychotic agents, cause serious extrapyramidal diseases as side effects, which has been a serious problem.
On the other hand, recently found dopamine D4 receptors are similar to dopamine D2 receptors in structure and properties but are utterly different from dopamine D2 receptors in intracerebral distribution. The intracerebral distribution of dopamine D4 receptors is such that they are present in a high concentration in cerebral cortex frontal lobe concerned with the onset of schizophrenia and are present in a low concentration in striatum involved in the onset of extrapyramidal diseases. Therefore, unlike the dopamine D2 receptor antagonists, dopamine D4 receptor antagonists are very likely to become novel therapeutic agents for schizophrenia which do not cause extrapyramidal diseases as side effects (Nature, 350, 610-614(1991); Nature, 358, 109(1992); Nature 365, 393(1993); Nature 365, 441-445(1993)).
As such a compound, there is clozapine. It has been reported that the affinity of clozapine for dopamine D4 receptors is higher than that for dopamine D2 receptors (Nature, 350, 610-614(1991)). It has also been reported that in clinical investigation of clozapine, unlike the dopamine D2 receptor antagonists, clozapine is effective on drug-resistant schizophrenia and negativism and hardly causes extrapyramidal diseases (Arch. Gen. Psych., 45, 789-796(1988)). Clozapine, however, causes a blood disease called agranulocytosis and deaths due to this disease have been reported (Summary and Clinical Data. Sandoz, Canada Inc. (1990)), and this is an serious defect of clozapine.
Accordingly, dopamine D4 receptor antagonists which do not have such a side effect are very useful as therapeutic agents for schizophrenia and the like which are very unlikely to cause extrapyramidal diseases.
An object of the present invention is to provide a dopamine D4 receptor antagonistic compound which has antipsychotic effect without causing extrapyramidal diseases.
The present inventors earnestly investigated arylpiperidine derivatives and consequently found novel arylpiperidine derivatives having a high affinity for dopamine D4 receptors, whereby the present invention has been accomplished.
The present invention is explained below.
The present invention is an arylpiperidine derivative represented by the formula (I): 
[wherein D is a carbon atom or a nitrogen atom, E is a CH group or a nitrogen atom, G is an oxygen atom, a sulfur atom, a nitrogen atom or an NH group, Y1 is a hydrogen atom or a halogen atom, n is an integer of 1 to 4, and R1 is a group represented by the formula (i): 
(wherein R2 is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an amino group, a monoalkylamino group of 1 to 5 carbon atoms, a hydroxyl group, an alkoxycarbonyl group of 2 to 6 carbon atoms, a carbamoyl group, a carboxyl group, or a metal salt of carboxyl group, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), a group represented by the formula (ii): 
(wherein R3 is an alkyl group of 1 to 5 carbon atoms, each of X1 and X2, which are different from each other, is a nitrogen atom or an NH group, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), a group represented by the formula (iii): 
(wherein X1 and X2 are as defined above, and Ar is a substituted or unsubstituted phenyl group or a thienyl group), or a group represented by the formula (iv): 
(wherein R4 is a hydrogen atom, a mercapto group, or an alkylthio group of 1 to 5 carbon atoms, and Ar is a substituted or unsubstituted phenyl group or a thienyl group)] or a pharmaceutically acceptable salt thereof.
In the present invention, the substituted phenyl group refers to a phenyl group having one or two substituents selected from halogen atoms, alkyl groups of 1 to 5 carbon atoms, alkoxy groups of 1 to 5 carbon atoms and trifluoromethyl group, and is, for example, a 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 4-chlorophenyl group, 4-bromophenyl group, 3,4-dichlorophenyl group, 4-methylphenyl group, 3,4-dimethylphenyl group, 4-methoxyphenyl group, 3,4-dimethoxyphenyl group, 2-trifluoromethylphenyl group, 3-trifluoromethylphenyl group or 4-trifluoromethylphenyl group.
The halogen atom is a fluorine atom, chlorine atom, bromine atom or iodine atom.
The alkyl group of 1 to 5 carbon atoms is a linear, branched or cyclic alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, cyclopropylmethyl, pentyl, isopentyl or the like.
The alkoxy group of 1 to 5 carbon atoms is a linear or branched alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentoxy, 3-methylbutoxy or the like.
The monoalkylamino group of 1 to 5 carbon atoms is, for example, a methylamino group, ethylamino group, propylamino group, isopropylamino group or the like.
The alkylthio group of 1 to 5 carbon atoms is, for example, a methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group, isobutylthio group or the like.
The alkoxycarbonyl group of 2 to 6 carbon atoms is, for example, a methoxycarbonyl group, ethoxycarbonyl group, propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group or the like.
The pharmaceutically acceptable salt of the present invention is, for example, a salt with a mineral acid such as sulfuric acid, hydrochloric acid, phosphoric acid or the like, or a salt with an organic acid such as acetic acid, oxalic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, trifluoroacetic acid, methanesulfonic acid, pamoic acid, decanoic acid, enanthic acid or the like.
Arylpiperidine derivatives of the formula (I) in which R1 is represented by the formula (ii) or (iii) have tautomers due to their chemical structures, and the present invention includes these tautomers.
The compound of the present invention is preferably an arylpiperidine derivative represented by the formula (II): 
(wherein R2, Ar, D, E, G, Y1 and n are as defined above) or a pharmaceutically acceptable salt thereof.
Said compound is more preferably an arylpiperidine derivative represented by the formula (III): 
(wherein Y1 is as defined above, Y2 is a hydrogen atom or a halogen atom, J is an oxygen atom, a sulfur atom or an NH group, and R5 is an alkyl group of 1 to 5 carbon atoms, an amino group or a carbamoyl group) or a pharmaceutically acceptable salt thereof.
The compound of the formula (I) can be produced by any of the following processes.
In the following reaction formulas, Ar, D, E, G, R3, R4, X1, X2, Y1 and n are as defined in the above formula (I), R6 is a hydrogen atom, an alkyl group of 1 to 5 carbon atoms, an amino group, or a monoalkylamino group of 1 to 5 carbon atoms, R7 and R8 are taken together with the adjacent nitrogen atom to represent a pyrrolidino group, a piperidino group, a morpholino group, an N-methylpiperazino group or the like, Z is a chlorine atom, a bromine atom or an iodine atom, M1 is, for example, sodium, potassium or NH4, and M2 is an alkali metal ion (e.g. sodium, potassium, lithium or calcium), an alkaline earth metal ion or a hydrogen atom. 
A ketone derivative (1) is halogenated with a halogenating agent in an inert solvent and then reacted with a thiourea derivative or thioamide derivative of the formula (2) or with a urea derivative or amide derivative of the formula (3) and a sulfurizing agent, in an inert solvent in the presence or absence of a dehydrating agent to obtain a compound (4). Subsequently, the compound (4) is reacted with a piperidine derivative of the formula (5) in an inert solvent in the presence of a base to obtain a compound (6) of the present invention.
In each of these reactions, the inert solvent is, for example, an organic carboxylic acid such as acetic acid; an organic halide such as chloroform or carbon tetrachloride; an alcohol such as ethanol or isopropanol; an ether such as tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; a ketone compound such as acetone or methyl ethyl ketone; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. The halogenating agent is, for example, chlorine, bromine, iodine or sulfuryl chloride.
The dehydrating agent is, for example, a molecular sieves such as molecular sieves 3A or molecular sieves 4A; an inorganic salt such as anhydrous magnesium sulfate, anhydrous calcium sulfate or anhydrous calcium chloride; or phosphorus pentaoxide. The sulfurizing agent is, for example, phosphorus pentasulfide or Lawesson""s reagent. The base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an alcoholate such as sodium ethoxide; an alkali metal amide such as sodium amide; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate. 
A ketone derivative (1) is halogenated with a halogenating agent in the same manner as in the reaction formulas 1 and reacted with a thiocyanate (7) in an inert solvent, and the reaction product is subjected to acid treatment to obtain a 2-hydroxythiazole derivative (8).
In the reaction, the inert solvent is, for example, an organic carboxylic acid such as acetic acid; an organic halide such as carbon tetrachloride or chloroform; an alcohol such as ethanol or isopropanol; an ether such as diethyl ether or tetrahydrofuran; a hydrocarbon such as toluene; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. The acid treatment is treatment with one of or a mixture of two or more of acids such as hydrochloric acid, sulfuric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, etc. in an alcohol (e.g. methanol or ethanol), an ether (e.g. dioxane) or water.
Then, the compound (8) is reacted with a piperidine derivative (5) in an inert solvent in the presence of a base to obtain a compound (9) of the present invention.
In this reaction, the inert solvent is, for example, an alcohol such as ethanol or isopropanol; an ether such as tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; a ketone compound such as acetone or methyl ethyl ketone; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. The base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an alcoholate such as sodium ethoxide; an alkali metal amide such as sodium amide; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate. 
A ketone derivative (1) is hydrogenated with a hydrogenating agent in the same manner as in the reaction formulas 1 and then reacted with a thioamide derivative (10) in an inert solvent in the presence or absence of a dehydrating agent to obtain a thiazole derivative (11). Subsequently, the compound (11) is reacted with a piperidine derivative (5) in an inert solvent in the presence of a base to obtain a compound (12) of the present invention.
In each of these reactions, the inert solvent is, for example, an alcohol such as ethanol or isopropanol; an ether such as tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; a ketone compound such as acetone or methyl ethyl ketone; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. The base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an alcoholate such as sodium ethoxide; an alkali metal amide such as sodium amide; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate.
The compound (12) can be converted to a compound (13) of the present invention by treatment with ammonia in an inert solvent.
In this reaction, the inert solvent is, for example, an ether such as diethyl ether, tetrahydrofuran or dioxane; an alcohol such as methanol or ethanol; acetonitrile; or water. 
The ester group of a compound (12) is hydrolyzed in an inert solvent in the presence of a base or an acid to obtain a compound (14) of the present invention.
In this reaction, the inert solvent is, for example, an ether such as diethyl ether, tetrahydrofuran or dioxane; an alcohol such as methanol or ethanol; a ketone such as acetone; an organic carboxylic acid such as acetic acid; N,N-dimethylformamide; or water. The base is, for example, an inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide, calcium hydroxide or sodium carbonate. The acid is, for example, an inorganic acid such as hydrochloric acid, hydrobromic acid or sulfuric acid; or an organic acid such as trifluoroacetic acid, formic acid, p-toluenesulfonic acid or methanesulfonic acid. 
A ketone derivative (1) is halogenated with a halogenating agent in the same manner as in the reaction formulas 1 and reacted with an S-alkylisothiourea derivative (15) in an inert solvent in the presence of a base to obtain an imidazole derivative (16). Then, the compound (16) is reacted with a piperidine derivative (5) in an inert solvent in the presence of a base to obtain a compound (17) of the present invention.
In each of these reactions, the inert solvent is, for example, an alcohol such as ethanol or isopropanol; an ether such as tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; a ketone compound such as acetone or methyl ethyl ketone; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. The base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an alcoholate such as sodium ethoxide; an alkali metal amide such as sodium amide; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate. 
A ketone derivative (1) is reacted with a piperidine derivative (5) in an inert solvent or without a solvent in the presence or absence of a base to obtain an aminoketone (18).
In this reaction, the base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate. The inert solvent is, for example, an ether such as diethyl ether, tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; or an alcohol such as ethanol.
Then, the aminoketone (18) is reacted with an N,N-dimethylformamide dialkylacetal (19) in an inert solvent in the presence of a cyclic amine to obtain an enamine derivative (20), which is reacted with hydrazine to obtain a compound (21) of the present invention.
In the former reaction, the cyclic amine is, for example, pyrrolidine, piperidine, morpholine or N-methylpiperazine. The inert solvent is, for example, an ether such as tetrahydrofuran or dioxane; a hydrocarbon such as benzene or toluene; acetonitrile; or N,N-dimethylformamide. A solvent used in the reaction with hydrazine is, for example, an alcohol such as methanol, ethanol or isopropanol; an ether such as diethyl ether or tetrahydrofuran; a hydrocarbon such as toluene; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof. 
An enamine derivative (20) is reacted with a mixture of formamide and ammonium formate (22), thiourea (23) or an S-alkylisothiourea (14) in an inert solvent optionally in the presence of a base to obtain a compound (24) of the present invention.
In this reaction, the base is, for example, an organic amine such as triethylamine, diisopropylethylamine or pyridine; an inorganic base such as sodium hydrogencarbonate, sodium carbonate, potassium carbonate, sodium hydroxide or sodium hydride; or an organic acid salt such as sodium acetate. The inert solvent is, for example, an organic carboxylic acid such as acetic acid; an organic halide such as carbon tetrachloride or chloroform; an alcohol such as ethanol or isopropanol; an ether such as diethyl ether or tetrahydrofuran; a hydrocarbon such as toluene; N,N-dimethylformamide; acetonitrile; water; or a mixed solvent thereof.
The compound of the present invention has a high affinity for dopamine D4 receptors but has a low affinity for dopamine D2 receptors, namely, said compound has an excellent selectivity. Therefore, the compound of the present invention is useful as a prophylactic and therapeutic agent for diseases such as schizophrenia and problem behaviors associated with cerebrovascular diseases or senile dementia, and is useful as a drug that does not cause extrapyramidal diseases as side effects.
For the purposes described above, the compound of the present invention can be formulated into tablets, pills, capsules, granules, a powder, solution, emulsion, suspension, injection or the like by a conventional preparation technique by adding conventional additives such as an extender, binder, disintegrator, pH adjustor, solubilizer, etc.
The compound of the present invention can be administered to an adult patient orally or parenterally in a dose of 0.1 to 500 mg per day in one portion or several portions. The dose may be properly varied depending on the kind of a disease and the age, body weight and symptom of the patient.
The present invention is concretely explained with the reference to the following examples and test example.